- Synthesis and anti-tumor activity evaluation of salinomycin C20-O-alkyl/benzyl oxime derivatives
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Seventeen C20-O-alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC50 values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca2+ concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20-O-alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.
- Duan, Wenfang,Hao, Jie,Hu, Yuhua,Li, Bo,Li, Tianlei,Li, Zhongwen,Lian, Xu,Qin, Tong,Tang, Lei,Wu, Jun,Wu, Song,Zhang, Chi,Zhang, Jihong,Zhang, Wenxuan,Zhao, Xintong
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p. 870 - 876
(2022/02/03)
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- Structure-activity relationships of pyrimidine nucleotides containing a 5′-α,β-methylene diphosphonate at the P2Y6 receptor
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The Gq-coupled P2Y6 receptor (P2Y6R) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2Y6R agonist and P2Y14R partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2Y6R agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5′-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2Y6R potency (MRS4554, 0.57 μM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2Y14R, respectively. However, 3-alkyl (31–33, 37, 38), β-D-arabinofuranose (39) and 6-aza (40) substitution prevented P2Y6R activation. Thus, we have identified new α,β-methylene bridged N4-extended CDP analogues as P2Y6R agonists that are highly selective over the P2Y14R.
- Dobelmann, Clemens,Gopinatth, Varun,Jacobson, Kenneth A.,Jain, Shanu,Junker, Anna,Oliva, Paola,Phung, Ngan B.,Scortichini, Mirko,Toti, Kiran S.
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supporting information
(2021/06/15)
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- Preparation method of benzyloxyamine hydrochloride
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The invention discloses a preparation method of benzyloxyamine hydrochloride. The preparation method comprises the following steps: (1) dispersing ketoxime 2 and alkali metal hydroxide into a mixed solvent of dimethylacetamide and water at the temperature of 50-55 DEG C and the stirring speed of 100-120 rpm; (2) dropwise adding a benzyl halide compound 1 into a dispersion body obtained in the step (1), reacting for 130-140 minutes at the temperature of 60-65 DEG C after dropwise adding is completed, then cooling to room temperature, adding water, extracting by using normal hexane, and distilling an organic phase under reduced pressure to obtain a product 3; and (3) adding the product 3 obtained in the step (2) into a mixed solution of methanol and a hydrochloric acid solution with the mass concentration of 38% , reacting for 200-220 minutes at the temperature of 35-40 DEG C and at the stirring speed of 80-100 rpm, distilling under reduced pressure until a solid is separated out, cooling to room temperature, washing the solid with petroleum ether, and drying to obtain the target product 4-benzyloxyamine hydrochloride. According to the preparation method, the total yield can reach 95% or above, and the product purity can reach 99% or above.
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Paragraph 0047-0049; 0052
(2021/04/14)
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- Vinylogous Aza-Michael Addition of Urea Derivatives with p-Quinone Methides Followed by Oxidative Dearomative Cyclization: Approach to Spiroimidazolidinone Derivatives
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Herein, we report an efficient protocol for the synthesis of spiro-imidazolidinone-cyclohexadienones from p-quinone methides (p-QMs) and dialkyloxy ureas under mild conditions. The strategy follows a two-step process involving an initial vinylogous conjugate addition of urea derivatives to p-QMs, followed by oxidative dearomative cyclization of open-chain product to the projected spiro-imidazolidinones. This protocol exhibits good functional group tolerance and provides a straightforward method to access spiro-imidazolidinone-cyclohexadienones. In follow-up chemistry, we have shown the debenzylation of spiroimidazolidinones to give N-hydroxycyclic ureas. (Figure presented.).
- Kaur, Navpreet,Singh, Priyanka,Banerjee, Prabal
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p. 2813 - 2824
(2021/04/21)
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- Synthesis and antibacterial evaluation of (E)-1-(1H-indol-3-yl) ethanone O-benzyl oxime derivatives against MRSA and VRSA strains
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Infections caused due to multidrug resistant organisms have emerged as a constant menace to human health. Even though numerous antibiotics are currently available for treating infectious diseases, a great number of bacterial strains have acquired resistance to many of them. Among these, infections caused due to Staphylococcus aureus are predominant in adult and paediatric population. Indole is a prominent chemical scaffold found in many pharmacologically active natural products and synthetic drugs. A number of oxime ether containing compounds have attracted attention of researchers owing to their interesting biological properties. Current work details the synthesis of indole containing oxime ether derivatives and their evaluation for antimicrobial activity against a panel of bacterial and mycobacterial strains. Synthesized compounds demonstrated good to moderate activity against drug-resistant S. aureus including resistant to vancomycin. Among all, compound 5h was found to possess potent activity against susceptible as well as MRSA and VRSA strains of S. aureus with MIC of 1 μg/mL and 2–4 μg/mL respectively. In addition, compound 5h was found to be non-toxic to Vero cells and exhibited good selectivity index of >40. Further, 5h, E-9a and E-9b possessed good biofilm inhibition against S. aureus. With these assuring biological properties, synthesized compounds could be potential prospective antimicrobial agents.
- Akunuri, Ravikumar,Veerareddy, Vaishnavi,Kaul, Grace,Akhir, Abdul,Unnissa, Tanveer,Parupalli, Ramulu,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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supporting information
(2021/08/27)
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- Palladium-catalyzed regio- And stereoselective access to allyl ureas/carbamates: Facile synthesis of imidazolidinones and oxazepinones
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Typically, transition metal catalysis enforces the stereodefined outcome of a reaction. Here we disclose the palladium-catalyzed regio- and stereoselective access to allylic ureas/carbamates and their further exploitation to diverse cyclic structures under operationally simple reaction conditions. This protocol features palladium-catalyzed decarboxylative amidation of highly modular VECs with good to excellent yield, minimal waste production, wide substrate scope, and low catalyst loading. In follow-up chemistry, we demonstrated the debenzylation of vinylic imidazolidinones to N-hydroxycyclic ureas and regioselective derivatization towards the facile synthesis of halohydrins and oxiranes under mild reaction conditions in good to excellent yields. This journal is
- Banerjee, Prabal,Saha, Debarshi,Taily, Irshad Maajid
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p. 6564 - 6570
(2020/11/10)
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- O-benzyl-N-(9-acridinyl)hydroxylamines
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A series of O-benzyl-N-(9-acridinyl)hydroxylamines was prepared, isolated, and evaluated for biological activity using both thermal denaturation and MTT assays. Changes in the thermal denaturation temperature of genomic calf-thymus DNA ranged from +6.6 °C to +20.2 °C. MTT assays on SNB-19 glioblastoma cells provided biological activity that ranged from 17.4 μM to 33.2 μM. Both evaluation methods of biological activity indicate that substitution of the benzyl group by either electron-withdrawing or electron-donating groups provides a measureable benefit in these assays. The two assays agreed on the magnitude of the interaction for each substitution pattern.
- Johnson, Alyssa L.,Duncan, Nathan,Mosher, Michael D.
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p. 139 - 148
(2018/06/27)
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- Direct cycle between co-product and reactant: An approach to improve the atom economy and its application in the synthesis and protection of primary amines
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Two important goals of green chemistry are to maximize the efficiency of reactants and to minimize the production of waste. In this study, a novel approach to improve the atom economy of a chemical process was developed by incorporating a direct cycle between a co-product and a reactant of the same reaction. To demonstrate this concept, recoverable 3,4-diphenylmaleic anhydride (1) was designed and used for the atom-economical synthesis of aliphatic primary amines from aqueous ammonia. In each individual cycle, only ammonia and alkyl halide were consumed, and 1 was recovered in nearly a quantitative yield. In this approach for developing atom-economical protecting agents, 1 showed good performance as a recoverable protecting agent for primary amines. The broad substrate scope, good tolerance to various reaction conditions, and high reaction and recovery rates make 1 a valuable complement to conventional primary amine protecting agents.
- Guan, Qi,Jiang, Mingyang,Wu, Junhui,Zhai, Yanpeng,Wu, Yue,Bao, Kai,Zhang, Weige
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supporting information
p. 5794 - 5799
(2016/11/06)
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- O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1
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Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.
- Malachowski, William P.,Winters, Maria,DuHadaway, James B.,Lewis-Ballester, Ariel,Badir, Shorouk,Wai, Jenny,Rahman, Maisha,Sheikh, Eesha,LaLonde, Judith M.,Yeh, Syun-Ru,Prendergast, George C.,Muller, Alexander J.
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p. 564 - 576
(2016/01/09)
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- NOVEL VASCULAR LEAKAGEAGE INHIBITOR
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The present disclosure relates to a novel vascular leakage inhibitor. The novel vascular leakage inhibitor of the present invention inhibits the apoptosis of vascular endothelial cells, inhibits the formation of actin stress fibers induced by VEGF, and enhances the cortical actin ring structure, thereby inhibiting vascular leakage. Accordingly, the vascular leakage inhibitor of the present invention can prevent or treat various diseases caused by vascular leakage. Since the vascular leakage inhibitor of the present invention is synthesized from commercially available or easily synthesizable pregnenolones, it has remarkably superior feasibility of commercial synthesis.
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Paragraph 0124
(2015/01/07)
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- Synthesis and in vitro cytotoxic activity of N-2-(2-furyl)-2- (chlorobenzyloxyimino) ethyl ciprofloxacin derivatives
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Quinolone are a class of potent broad-spectrum antibacterial drugs that target the bacterial type II DNA topoisomerases (DNA gyrase) and topoisomerase IV. In the present study, the synthesis and evaluation of cytotoxicity activity of a new series of N-pipearzinyl quinolones containing N-2-(furyl-2-yl)-2- (chlorobenzyloxyimino) ethyl moiety (6a-c) have been studied. Preliminary screening showed that one of the new compounds, namely 7-(4-(2-(3- chlorobenzyloxyimino)-2-(furan-2-yl) ethyl) piperazin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (6b) showed significant cytotoxic activity against human breast tumor cell lines.
- Alipour, Eskandar,Mohammadhosseini, Negar,Panah, Fatemeh,Ardestani, Sussan K.,Safavi, Maliheh,Shafiee, Abbas,Foroumadi, Alireza
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scheme or table
p. 1226 - 1231
(2012/06/30)
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- Synthesis and fungicidal activity of macrolactams and macrolactones with an oxime ether side chain
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Three series of novel macrolactams and macrolactones - 12-alkoxyimino- tetradecanlactam, 12-alkoxyiminopentadecanlactam, and 12-alkoxyiminodecanlactone derivatives (7A, 7B, and 7C) - were synthesized from corresponding 12-oxomacrolactams and 12-oxomacrolactone. Their structures were confirmed by 1H NMR and elemental analysis. The Z and E isomers of 7A and 7B were separated, and their configurations were determined by 1H NMR. These compounds showed fair to excellent fungicidal activities against Rhizoctonia solani Kuehn. It is interesting that the Z and E isomers of most of the compounds have quite different fungicidal activities. The fact that the compounds have a gradual increase of fungicidal activity in the order of 7A, 7C, and 7B indicated that the macrocyclic derivatives with a hydrogen-bonding acceptor (=N-O-) and a hydrogen-bonding donor (-CONH-) on the ring, and a three methylenes distance (CH2CH2CH2) between these two functional groups, exhibited the best fungicidal activity. The bioassay also showed that 7B not only has good fungicidal activity but also may have a broad spectrum of fungicidal activities.
- Huang, Jia-Xing,Jia, Yue-Mei,Liang, Xiao-Mei,Zhu, Wei-Juan,Zhang, Jian-Jun,Dong, Yan-Hong,Yuan, Hui-Zu,Qi, Shu-Hua,Wu, Jin-Ping,Chen, Fu-Heng,Wang, Dao-Quan
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experimental part
p. 10857 - 10863
(2009/11/30)
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